Lecture 6 Flashcards

1
Q

Lupus

A

2 forms: discoid lupus which only affects the skin and SLE which affects skin and joints and frequently involves internal organs (e.g heart and kidneys)

Cardiovascular problems are the leading cause of death in SLE. Common problems are pericarditis and pleurisy with accelerated atherosclerosis

Symptoms include joint pains, rashes, extreme fatigue, fever and swelling of lymph glands

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2
Q

Causes of SLE

A

Runs in families but no single gene identified as causal, susceptibility genes are known

Numerous environmental triggers e.g. UV radiation and viral infection

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3
Q

Immune abnormalities associated with SLE

A
  • defective clearing of apoptotic cells
  • increased response to AGs containing nucleic acids
  • decreased threshold of activation of autoAB producing Bcells

One theory is that defective clearing of apoptotic cells by macrophages results in APCs presenting apoptotic material as autoantigens resulting in anti-nuclear ABs (ANA) the main diagnostic tests for SLE involve blood tests against ANA and anti-dsDNA

Impaired NET degradation which would provide a further source of common SLE AGs such as histones

Increased levels of cytokines including TNFα, IL-6, interferons and B lymphocyte stimulator (BLyS important for B cell survival, differentiation and AB production)

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4
Q

Treatments for SLE

A
  • NSAIDs to reduce joint pains and fever
  • Hydroxychloroquine reduces inflammation likely by reducing interferon production
  • corticosteroids to reduce inflammation in flare ups
  • immunosuppressives e.g methotrexate and azathioprine
  • belimumab, anti-BLyS, sequestration of BLyS reduces B cell activity
  • Rituximab (limited trial evidence, many B cell subsets, CD20+ may not be that important in lupus)
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5
Q

When are immunosuppressive drugs used?

A

Autoimmune diseases and to avoid transplant rejection

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6
Q

How to corticosteroids exert an immunosuppressive effect?

A

Decrease the transcription of a variety of cytokines including those that drive Th proliferation (IL-2) and inflammatory responses (e.g. IL-1 and TNFα).

Also upregulate anti-inflammatory factors such as IL-1ra

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7
Q

Azathioprine

A

Prodrug for 6-mercaptopurine (6-MP) which is converted to thioinosic monophosphate (TIMP) by hypoxanthine phosphoribosyl transferase (HPRT)

TIMP converted to 2 different products
1. converted to 6-methyl-TIMP (MeTIMP) by thiopurine methyltransferase(TPMT). MeTIMP inhibits de novo purine synthesis

  1. converted to 6-thioguanosine nucleotides (6-TGN) via inosine monophosphate dehydrogenase (IMPDH). This inhibits nucleotide and protein synthesis

These effects inhibit cellular proliferation especially in cells that lack the ability to synthesise nucleotides from intermediates of nucleotide degradation such as T and B cells

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8
Q

Side effects of azathioprine

A

GI disturbance, bone marrow suppression and hepatotoxicity

Levels of TPMT vary, 10% of people have very low levels leading to accumulation of cytotoxic 6-thioguanine nucleotide and associated toxicity

can be prevented by monitoring TPMT levels

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9
Q

Methotrexate

A

Folic acid antagonist.

Targets rapidly proliferating cells such as immune cells and therefore can be used as an immunosuppressant

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10
Q

Mycophenolic acid

A

Derived from the fungus penicillum stoloniferum and inhibits IMPDH which is crucial for de novo synthesis of guanosine (greatest impact on B and T cells)

Mainly used in transplant rejections but also in autoimmune disease such as myasthenia gravis

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11
Q

Cyclophosphamide

A

Commonly used alkylating agent which is a prodrug
Converted to aldophosphamide by hepatic p450 enzymes

Then converted to active phosphoramide mustard which has 2 alkylating groups and cross links guanine in DNA via N7 groups

1) bischloroethylamine undergoes cyclisation releasing Cl- and forms an unstable immonium cation
2) the strained ring opens to form a reactive carbonium ion
3) carbonium ion reacts with guanine’s N7 to produce 7-alkylguanine
4) 7-alkylguanine pairs with thymine producing substitution of A-T for G-C
it can also induce guanine excision and chain breakage

This kills rapidly dividing T and B cells

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12
Q

Side effects of cyclophosphamide

A

Bone marrow suppression
Potential infertility
Bladder irritation (TRPA1)and cancer
Some other forms of cancer e.g. lymphoma

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13
Q

What is cyclophosphamide used to treat?

A

Refractory autoimmune conditions and some cancers

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14
Q

Cyclosporin A (CsA)

A

Immunosuppressant isolated from the fungus tolypocladium inflatum

CsA is a cyclic 11 amino acid peptide whose predominant action is to prevent T cell proliferation via suppression of IL-2 synthesis

CsA binds to a cytoplasmic protein called cyclophilin (CpN). The CsA-CpN complex binds to and inhibits calcineurin (a ser-thr phosphatase). This prevents the dephosphorylation of the nuclear factor of activated T cells (NF-AT) and therefore prevents it from entering the nucleus thus preventing IL-2 upregulation

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15
Q

Tacrolimus

A

A macrolide antibiotic

Binds to an immunophilin called FK-binding protein which in complex with tacrolimus inhibits calcineurin, thus NF-AT is retained and IL-2 upregulation is inhibited

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16
Q

basiliximab

A

mAB against CD25 α subunit of the IL-2 receptor and therefore functions as an IL-2 receptor antagonist

IL-2 upregulated in activated B and T cells therefore basiliximab used to prevent acute transplant rejection

17
Q

Belatacept

A

Fusion protein of the extracellular domain of CTLA-4 and the Fc fragment of human IgG

belatacept binds CD80/86 to prevent T cell costimulation

18
Q

TGN1412

A

anti-CD28 agonist mAB was trialled after it was shown that CD28 alone can cause activation and proliferation of T cells

Trial as ended abruptly after the drug induced a cytokine storm due to non-selective effects

19
Q

Sirolimus mechanism

A

also called rapamycin

Macrolide antibiotic which binds FKBP (like tacrolimus) However it does not inhibit CaN, instead inhibits mammalian target of rapamycin (mTOR) which is a ser/thr kinase involved in cell cycle progression and protein synthesis

Reduces T cell activation and proliferation

20
Q

Uses of sirolimus

A

Prevention of transplant rejection

Coating of coronary stents to prevent restenosis